Summary
What is already known about this topic?
Fleaborne typhus, a vectorborne zoonosis caused by Rickettsia
typhi, is a moderately severe but rarely fatal illness.
What is added by this report?
Fleaborne typhus cases in Los Angeles County (LAC), California increased from 31 in
2010 to 171 in 2022. In 2022, three associated deaths occurred among LAC adults with
underlying medical conditions; severe manifestations included hemophagocytic lymphohistiocytosis,
myocarditis, and septic shock.
What are the implications for public health practice?
Health care providers should suspect fleaborne typhus in patients with compatible
symptoms who live in or travel to areas with endemic disease or are exposed to reservoir
animals; prompt initiation of doxycycline therapy is critical. Monitoring rodent,
opossum, free-roaming cat, and dog flea infestations and the numbers of infected fleas
is needed to understand disease ecology and more efficiently direct interventions
to prevent disease in humans.
Abstract
Fleaborne typhus (also known as murine typhus), a widely distributed vectorborne zoonosis
caused by Rickettsia typhi, is a moderately severe, but infrequently fatal illness;
among patients who receive doxycycline, the case-fatality rate is <1%. Fleaborne typhus
is a mandated reportable condition in California. Reported fleaborne typhus cases
in Los Angeles County have been increasing since 2010, with the highest number (171)
reported during 2022. During June–October 2022, Los Angeles County Department of Public
Health learned of three fleaborne typhus–associated deaths. This report describes
the clinical presentation, illness course, and methods used to diagnose fleaborne
typhus in these three cases. Severe fleaborne typhus manifestations among these cases
included hemophagocytic lymphohistiocytosis, a rare immune hyperactivation syndrome
that can occur in the infection setting; myocarditis; and septic shock with disseminated
intravascular coagulation. Increased health care provider and public health awareness
of the prevalence and severity of fleaborne typhus and of the importance of early
doxycycline therapy is essential for prevention and treatment efforts.
Introduction
Fleaborne typhus is transmitted from infected fleas by inoculation of flea feces into
the flea bite site, a skin abrasion, or mucous membranes (
1
). The Oriental rat flea (Xenopsylla cheopis), a parasite of rats, is the historical
vector (
2
). The cat flea (Ctenocephalides felis), whose principal host is the domestic cat
(but which is also found on opossums, dogs, and rats) is the predominant vector in
suburban areas of the United States* (
3
). Signs and symptoms of fleaborne typhus include fever, headache, a palm- and sole-sparing
rash, hepatitis, and thrombocytopenia (
4
). Approximately one third of infected patients require intensive care for associated
aseptic meningitis, seizures, adult respiratory distress syndrome, or septic shock
(
4
); however, among patients who receive doxycycline therapy, the case-fatality rate
is <1% (
5
). Most current cases in the United States are identified in California, Hawaii, and
Texas (
4
). During 1985–2015, among 3,048 fleaborne typhus cases in Texas, 11 (0.4%) were fatal
(
6
). The disease is endemic in Los Angeles County (LAC), and reporting is mandated in
California (Figure). Before 2022, the most recent fleaborne typhus–associated death
in LAC was reported in 1993.
FIGURE
Fleaborne typhus cases, by year — Los Angeles County, California* 2010–2022
* Excluding the cities of Pasadena and Long Beach; data include confirmed, probable,
and suspected cases.
The figure is a histogram of the number of fleaborne typhus cases, by year, in Los
Angeles County, California, during 2010–2022.
Methods
As part of fleaborne typhus surveillance in LAC, retrospective medical record review
and case or next-of-kin interviews are conducted for all reported cases with presumptive
or confirmatory laboratory evidence of infection. A presumptive fleaborne typhus case
includes detection of R. typhi immunoglobulin (Ig) G antibodies at titers ≥1:128 or
IgM titers ≥1:256 by indirect immunofluorescence antibody assay obtained from specimens
collected within 60 days of illness onset.
†
Additional testing was performed at the California Department of Public Health Viral
and Rickettsial Disease Laboratory for severe or fatal cases, and those in which clinical
criteria were met but antibody titers were below case definition thresholds. Two types
of real-time polymerase chain reaction (PCR) assays were used, one that identified
a 119-base-pair (bp) repeat region within the gene for surface cell antigen 2 (an
autotransporter protein), or at the Rickettsial Zoonoses Branch at CDC, an assay that
amplified 146-bp or 197-bp fragments of intergenic regions of R. typhi.
For the reported deaths in 2022, autopsy findings were reviewed to confirm the cause
of death. Testing for R. typhi antigens using an immunohistochemical stain was performed
on tissues of one patient with fatal fleaborne typhus obtained at autopsy (
7
). This activity was reviewed by CDC and conducted consistent with applicable federal
law and CDC policy.
§
Results
Case Series
Patient A. In June 2022, a man identifying as Hispanic
¶
aged 68 years was evaluated in an emergency department (ED) for a 3-day history of
fever and progressive lower extremity weakness (Table). Medical history included diffuse
lymphadenopathy, obesity, hypertension, diabetes mellitus type 2, and peripheral vascular
disease complicated by a chronic left foot ulcer. He had anemia and elevated liver
enzymes and was admitted to the hospital with a diagnosis of sepsis and treated with
broad-spectrum antibiotics. His mental status deteriorated, and he became difficult
to rouse. On hospital day 8, he experienced hypotension and atrial fibrillation with
rapid ventricular response and was transferred to the intensive care unit. The next
day, he experienced hypoxemic respiratory failure and was placed on mechanical ventilation;
the day after, he required vasopressor support and was given stress-dose steroids.
On hospital day 9, a bone marrow biopsy was notable for scattered hemophagocytosis
(histiocytic phagocytosis of red blood cells, white blood cells, platelets, and their
precursors), and on hospital day 16, he received a diagnosis of hemophagocytic lymphohistiocytosis
(HLH), a rare immune system disease, for which he received chemotherapy and infection
prophylaxis as indicated by HLH-2004 protocol (
8
). He received doxycycline on hospital day 18, after receiving a positive Karius test**
result for R.
typhi. On hospital day 24, he no longer required mechanical ventilation, was extubated,
and remained minimally responsive. On hospital day 29, he experienced multiorgan failure
and transitioned to comfort care; he died on hospital day 30. Death was attributed
to fleaborne typhus–induced HLH and septic shock. Potential exposure to rodents and
fleas included proximity of the patient’s home to a highway and litter.
TABLE
Demographic, epidemiologic, and clinical characteristics of persons who died from
fleaborne typhus–related illness — Los Angeles County, California, June–October 2022
Characteristic
Patient
A
B
C
Age, yrs (sex)
68 (male)
49 (female)
71 (male)
Ethnicity*
Hispanic
Hispanic
Hispanic
Signs and symptoms
Fever for 3 days and progressive lower extremity weakness
Headache, fever, chills, night sweats, and back pain for 7 days
Fever, disorientation, hypotension, AF with rapid ventricular response, and petechial
rash (on legs and torso)
Potential exposure
Proximity of the patient’s home to a highway and litter
Stray kittens in patient’s backyard
Lived in an encampment inhabited by persons experiencing homelessness
Underlying medical conditions
Diffuse lymphadenopathy, obesity, hypertension, DM type 2, PVD, and chronic left foot
ulcer
Obesity, hypertension, hyperlipidemia, and DM type 2
Alcohol and methamphetamine use
Abnormal laboratory values (referent range)
White blood cell count (4.5–10.0/μl)
—†
—†
3.4
Immature neutrophils (<10%)
—†
—†
15
Platelet count (160–360/μl)
—†
130
31
Hemoglobin (13.5–16.5/μl)
10.4
—†
10.1
Sodium (135–145 mmol/L)
126
—†
—†
Potassium (3.5–5.1 mmol/L)
—†
2.8
—†
Magnesium (1.6–2.6 per md/dL)
—†
1.5
—†
Total bilirubin (<1 mg/dL)
—†
—†
1
Alanine aminotransferase (10–50 U/L)
143
114
73
Aspartate aminotransferase (10–50 U/L)
102
141
224
Venous lactate (0.5–1.6 mmol/L)
2.6
—†
4.8
C-reactive protein (<0.3 mg/L)
—†
269.2
—†
Treatments received
Cefepime, vancomycin, piperacillin-tazobactam, etoposide, dexamethasone, fluconazole,
and trimethoprim-sulfamethoxazole
Ceftriaxone, vancomycin, and meropenem
Ceftriaxone, vancomycin, acyclovir, and penicillin
Doxycycline therapy started, hospital day
18
2
2
Major clinical events
Mental status deterioration, hypotension, AF with rapid ventricular response, hypoxic
respiratory failure, HLH, and severe septic shock
SVT, two episodes of cardiac arrest, and multiorgan failure
Hypoxemic respiratory failure, multiorgan failure, and DIC
Microbiology results
Epstein-Barr virus infection diagnosed by PCR (hospital days 9 and 16), HSV 1 diagnosed
by bronchoscopy specimen, (hospital day 16), multidrug resistant Escherichia coli
detected in blood cultures, and CMV diagnosed by PCR (hospital day 29)
Parvovirus B19 DNA was detected in blood and heart tissue by PCR
—†
Rickettsia typhi molecular testing results
Titer collection timing, hospital day
19
2
2
Titer result timing, hospital day
28
Patient deceased
Patient deceased
Titer result
IgM titer
>1:256
1:128
1:128
IgG titer
>1:256
1:64
>1:256
VRDL result
IgG titer
Not submitted
>1:1,024
Not submitted
PCR result
Not submitted
Positive
Positive
Karius test§
Timing, hospital day
18
Not submitted
Not submitted
Result
Positive for R. typhi
—†
—†
Days to death after hospitalization
30
3
5
Cause of death¶
Fleaborne typhus–induced HLH and septic shock
Myocarditis
Septic shock associated with shock liver, hyperkalemia, and lactic acidosis
Abbreviations: AF = atrial fibrillation; CMV = cytomegalovirus; DIC = disseminated
intravascular coagulation; DM = diabetes mellitus; HLH = hemophagocytic lymphohistiocytosis;
HSV = herpes simplex virus; Ig = immunoglobulin; PCR = real-time polymerase chain
reaction; PVD = peripheral vascular disease; SVT = supraventricular tachycardia; VRDL = Viral
and Rickettsial Disease Laboratory.
* Persons of Hispanic or Latino (Hispanic) origin might be of any race but are categorized
as Hispanic.
† Result within normal limits.
§ A noninvasive, rapid cell-free DNA-based diagnostic test capable of identifying
bacteria, mycobacteria, DNA viruses, fungi, and protozoa in blood. Host and microbial
cell-free DNA isolated from the patient’s blood specimen is sequenced then analyzed
using bioinformatics of DNA-based pathogen genomes. The test is useful for identifying
rare pathogens. https://kariusdx.com/
¶ As recorded on the death certificate.
Patient B. In August 2022, a woman identifying as Hispanic aged 49 years was evaluated
at an urgent care facility for a 2-day history of headache and fever. Medical history
included obesity, hypertension, hyperlipidemia, and diabetes mellitus type 2. During
that visit she received a negative SARS-CoV-2 test result and was given a prescription
for antihistamines and nasal steroids to treat presumed allergic rhinitis. Five days
later, she visited an ED with fever, chills, night sweats, headache, and back pain.
She received intravenous fluids and was discharged after symptomatic improvement.
She returned to the ED the next day where she was found to be thrombocytopenic, hypokalemic,
and had elevated liver enzymes; she was admitted to the hospital with a diagnosis
of sepsis; treatment with broad-spectrum antibiotics was initiated. On hospital day
2, she experienced supraventricular tachycardia and two episodes of cardiac arrest
with successful resuscitation. Cardiac catheterization found stress cardiomyopathy
and no coronary artery disease. In light of the patient’s headache, fever and elevated
transaminases, an infectious diseases physician recommended treatment with doxycycline,
which was started on hospital day 2, for possible fleaborne typhus. The patient subsequently
experienced multiorgan failure and died on hospital day 3. Autopsy confirmed myocarditis
as a proximate cause of death. Immunohistochemistry evaluation for typhus group Rickettsia
demonstrated rare, multifocal staining of rickettsial antigens in endothelial cells
in small blood vessels of the heart and less frequently in endothelial cells lining
the sinusoidal spaces of the liver (Supplementary Figure, https://stacks.cdc.gov/view/cdc/131262).
Potential flea exposure included stray kittens living in the patient’s backyard.
Patient C. In October 2022, a man identifying as Hispanic aged 71 years who was experiencing
homelessness and had a history of alcohol use disorder was brought to an ED by ambulance
after having been observed lying in the same place on the ground for 24 hours. He
was febrile, disoriented, hypotensive, tachypneic, and experiencing atrial fibrillation
with rapid ventricular response. He had anemia, thrombocytopenia, and a low white
blood cell count with a predominance of immature neutrophils, in addition to lactic
acidosis and elevated liver enzymes. He had a petechial rash on his legs and torso.
Treatment for suspected meningitis, fleaborne typhus, and neurosyphilis was initiated.
On hospital day 2, the patient became hypoxemic, and on hospital day 4, experienced
hypoxemic respiratory failure and was placed on mechanical ventilation. He experienced
worsening multiorgan failure and disseminated intravascular coagulation and transitioned
to comfort care; he died on hospital day 5. Causes of death listed on the death certificate
were septic shock associated with shock liver, hyperkalemia, and lactic acidosis.
The patient might have also been exposed to fleas and rodents at the encampment where
he lived.
Discussion
The identification of three fatal cases of fleaborne typhus in LAC in 2022 occurred
in the context of a marked increase in LAC cases in recent years. Texas is also experiencing
a substantial increase in the prevalence and geographic distribution of fleaborne
typhus (
4
). Although reports of HLH among patients with R. typhi infection are rare (
9
), these three fleaborne typhus-associated deaths highlight the range of potentially
severe manifestations of this infection, including HLH, myocarditis, and septic shock
with disseminated intravascular coagulation. A recent study noted a case-fatality
rate of <1% (
6
); in LAC, the case-fatality rate was noted to be 1.8% in 2022. It is likely that
given the overall increase in cases, more persons with severe disease and deaths were
identified. In addition, all three patients had comorbidities that might have placed
them at increased risk for severe disease. A change in the pathogenicity of R.
typhi, although possible, has not been documented and needs to be monitored.
One possible reason for the observed substantial increase in fleaborne typhus cases
in suburban areas is the prevalence of the cat flea (Ctenocephalides felis), an abundant
nonselective parasite vector that affects free-roaming as well as companion animals
(
4
). Another possible reason could be an increase in rodent reservoirs in urban and
suburban areas in LAC. The fact that fleaborne typhus is no longer a nationally notifiable
disease poses surveillance challenges across the United States.
††
R. typhi–induced myocarditis has been reported in areas with endemic transmission
(
10
) and should be considered when evaluating a patient with acute coronary syndrome
(a condition resulting from a sudden reduction of blood flow to the heart) and an
unexplained febrile illness from such an area.
All three fatal cases described in this report had positive R. typhi molecular testing
results, which confirmed recent fleaborne typhus infection. Commercial R. typhi PCR
testing is unavailable, and confirmation of fleaborne typhus relies upon evidence
of a fourfold increase in IgG antibody titers from acute to postconvalescent illness
phases.
Limitations
The findings in this report are subject to at least two limitations. First, it is
likely that only patients with severe disease are tested for R. typhi, and surveillance
is currently missing patients with milder disease who might not have access to or
seek medical care or receive testing for R.
typhi from their health care provider. Second, patients with R.
typhi infections were not followed after they were discharged from the hospital, leading
to the possibility that some deaths due to R.
typhi might have been missed.
Implications for Public Health Practice
No vaccine to prevent fleaborne typhus currently exists. Use of veterinarian-approved
flea control products on pets can reduce the risk for flea exposures to humans. Because
R. typhi testing during early illness might result in nondetectable or low antibody
titers, and waiting for convalescent titers inherently delays confirmation of diagnosis,
health care providers should initiate treatment with doxycycline as soon as fleaborne
typhus is suspected. In addition, health care providers should consider fleaborne
typhus in any patient with fever, headache, and rash, particularly if the patient
lives in or recently traveled to an area with endemic disease or had exposure to a
reservoir animal (e.g., rodents, opossums, or feral cats).
§§
Monitoring rodent, opossum, cat, and dog flea infestations and the numbers of infected
fleas is important to better understand disease ecology and more effectively direct
interventions to prevent human disease.